Project 1[unreadable] In this study we determined conditions leading to the development of colitis in mice with nucleotide-binding oligomerization domain 2 (NOD2) deficiency, a susceptibility factor in Crohn?s disease. We found that NOD2-deficient antigen-presenting cells (APCs) produced increased amounts of interleukin (IL)-12 in the presence of ovalbumin (OVA)-peptide and peptidoglycan or recombinant E.coli that express OVA-peptide (ECOVA). Furthermore, these APCs elicited heightened interferon?gamma (IFN-g) responses from co-cultured OVA-specific CD4+ T cells. We then demonstrated that NOD2-deficient mice adoptively transferred OVA-specific CD4+ T cells and administered intra-rectal ECOVA developed colitis associated with the expansion of OVA-specific CD4+ T cells producing IFN-g. Importantly, this colitis was highly dependent on Toll-like receptor 2 (TLR2) function since it was suppressed in NOD2 and TLR2 double deficient mice. Thus, NOD2-deficient mice become susceptible to colitis as a result of increased TLR2 responses when they have the capacity to respond to an antigen expressed by mucosal bacteria.[unreadable] [unreadable] [unreadable] Project 2:[unreadable] INOD1 (Nucleotide-binding oligomerization domain 1), an epithelial cell protein that detects a diaminopimelic acid-containing ligand derived from peptidoglycan, plays a major role in host defense against mucosal pathogens. Here we show that NOD1 ligand elicits epithelial cell production of large amounts of TH1 chemokines, particularly in the presence of interferon (IFN)-g. Surprisingly, such production depends mainly on activation of the IFN-stimulated gene factor 3 (ISGF3) rather than on the NF-kB signaling pathway; as a result, NOD1 induces IRF7 and IFN-b production. Corroborating in vivo studies show that NOD1-intact mice subjected to gene silencing of Stat1, an ISGF3 component, exhibit decreased CXCL10 responses and increased susceptibility to Helicobactor pylori infection such as that seen in NOD1-deficient mice.